Immediate allergic reactions to β-lactams: Diagnostic accuracy of skin tests
2
who are representative of the target user population) and to obtain continual input and feedback from these end users throughout the development cycle of the device being tested. 3,4 Second, because an orange was used as the injection test site, the interactive feature (ie, voice instructions) was disabled to avoid the provision of conflicting instructions to the participant (ie, to inject the device into the thigh). Hence, this may have diminished the purpose of usability evalua- tion—to reveal errors and problems with the device, particularly for this distinguishing feature, which is not available in other autoin- jectors. Third, this study also used a within-participants protocol, where each of the 28 participants tested the NEA 18 times in a row, likely increasing their familiarity with the new device (learning bias). This is particularly problematic because participants were subsequently asked to compare the NEA with EpiPen and Twinject (for which practice opportunities were not provided). Thus, repeti- tious testing with NEA likely predisposed participants to prefer the new device. Furthermore, preferences were based on recall of per- sonal experiences (whether participants knew of someone who had used an epinephrine autoinjector incorrectly) rather than on empir- ical findings. These methods likely resulted in biased comparisons (recall bias) and are also not a valid indication of safety or usability. Fourth, the primary objective of the study was to visually observe “needle injection success” (ie, whether the needle injected or re- tracted by checking for puncture in the paper placed on the orange). However, the authors claim that the NEA needle resides in the patient for less time than the other 2 products (EpiPen and Twinject) and thus may lessen the potential for injection site reactions (ie, pain, bruising, or bleeding). This statement is indefensible because the study did not perform a head-to-head comparison with existing autoinjectors to warrant this claim. Finally, it is important to iterate that neither of the analyses 1,2 evaluated the current EpiPen design (which has a needle protec- tion device that extends and locks into place once the dose is administered) or addressed the cost of the different devices, particularly for the voice-activated model. We also question the interpretation of findings because both studies appear to have conflict of interest: investigator salaries were funded by Intelli- ject in the first study, 1 whereas the same funder assisted with the preparation of the manuscript in the second study. 2 On the basis of the possible flaws outlined in these 2 articles, 1,2 we believe that further studies with rigorously designed head-to- head comparisons are needed before drawing any conclusions. SUSAN WASERMAN, MSC, MD, FRCPC* MONIKA KASTNER,PHD† *Division of Clinical Immunology and Allergy Department of Medicine McMaster University Hamilton, Ontario, Canada †Li Ka Shing Knowledge Institute of St. Michael’s Hospital University of Toronto Toronto, Ontario, Canada [email protected] 1. Guerlain S, Hugine A, Wang L. A comparison of 4 epinephrine autoinjector delivery systems: usability and patient preference. Ann Allergy Asthma Immunol. 2010;104:172–177. 2. Guerlain S, Wang L, Hugine A. Intelliject’s novel epinephrine autoinjector: sharps injury prevention validation and comparable analysis with EpiPen and Twinject. Ann Allergy Asthma Immunol. 2010;105:480 – 484. 3. Nielson J. Usability Engineering. New York, NY: Academic Press; 1993. 4. Kushniruk AW, Patel VL. Cognitive and usability engineering methods for the evaluation of clinical information systems. J Biomed Inform. 2004;37:56 –78. IMMEDIATE ALLERGIC REACTIONS TO -LACTAMS: DIAGNOSTIC ACCURACY OF SKIN TESTS -Lactam antibiotics are the most frequent cause of drug allergic reactions. During the last few decades, changes in prescribing habits have caused amoxicillin and amoxicillin-clavulanic to replace ben- zylpenicillin as the most frequently involved agents. 1 Skin tests with major (penicilloyl-polylysine [PPL]) and minor (minor determinant mixture [MDM]) penicillin determinants are considered the first diagnostic procedure in the assessment of immediate allergic reac- tions. 2,3 However, in the last few years several authors have de- scribed a decrease in the diagnostic sensitivity of these determi- nants. 1 This could be because a significant proportion of patients produce specific and selective antibodies against the side chain of amoxicillin or other -lactam antibiotics. 1 There is some contro- versy about what determinants should be included in the evaluation of an allergic reaction to -lactam. 3–5 We have evaluated the outcomes of skin tests with different -lactam determinants. In addition, we have assessed whether skin testing patterns are different in patients with reactions to benzylpen- icillin than in patients with reactions to aminopenicillins. Between April 1995 and June 2009, we included all patients who consulted our Allergy Unit because of a clinical history of an immediate allergic reaction (anaphylaxis or urticaria) to benzylpen- icillin or aminopenicillins. The study was approved by the ethics committee of the hospital, and informed written consent was ob- tained from all patients. To compare the results, the sample was divided into 2 groups: patients who had had a reaction to benzylpen- icillin (group A) and patients who had had a reaction to aminopeni- cillins (group B). A detailed clinical history was obtained from all the patients. Skin tests were performed as previously described, 3 with PPL (10 -5 M) and MDM (10 -2 M) (Allergopen, Allergopharma, JGKG, Reinbek, Germany, until 2006 and afterward from Diater, Madrid, Spain), benzylpenicillin (10.000 IU), and amoxicillin (20 mg/mL). Initially, skin prick tests were performed. A wheal larger than 3 mm with erythema was considered a positive result. If the skin prick test result were negative, intradermal tests were performed. A 3-mm change in the diameter of the initial wheal associated with flare was considered positive. A positive result to one or more determinants was consid- ered diagnostic. When skin test results were negative, a drug prov- ocation test with the suspected -lactam was performed under strict hospital surveillance. Specific IgE to benzylpenicillin and amoxicillin was performed with the CAP-FEIA System (Phadia, Uppsala, Sweden). The posi- tive cutoff value was 0.35 kUA/L or higher. One thousand thirty-one patients with a suspected immediate hypersensitivity reaction to BP or aminopenicillins were evaluated. Of them, 281 patients (27.2%) had a positive result in the study. Two hundred sixty-four patients (94%) had positive skin test results, and 16 patients (5.7%) had a positive challenge test result. Only 1 Disclosures: Dr Moreno has participated in a trial to validate a diagnostic product to -lactam allergy (DAP-REF CEIC:08/731) from Diater Company, although the research in this paper is not related in any way to compensation received from this company. All other authors do not have any conflict of interest. © 2011 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.anai.2011.05.007 VOLUME 107, JULY, 2011 89
Transcript of Immediate allergic reactions to β-lactams: Diagnostic accuracy of skin tests
I�T�rhzmmdtsnpavo
�ti
ciictdic
taGbsewtpeoh
wt
hOh1
pari
P
who are representative of the target user population) and to obtaincontinual input and feedback from these end users throughout thedevelopment cycle of the device being tested.3,4 Second, because anorange was used as the injection test site, the interactive feature (ie,voice instructions) was disabled to avoid the provision of conflictinginstructions to the participant (ie, to inject the device into the thigh).Hence, this may have diminished the purpose of usability evalua-tion—to reveal errors and problems with the device, particularly forthis distinguishing feature, which is not available in other autoin-jectors. Third, this study also used a within-participants protocol,where each of the 28 participants tested the NEA 18 times in a row,likely increasing their familiarity with the new device (learningbias). This is particularly problematic because participants weresubsequently asked to compare the NEA with EpiPen and Twinject(for which practice opportunities were not provided). Thus, repeti-tious testing with NEA likely predisposed participants to prefer thenew device. Furthermore, preferences were based on recall of per-sonal experiences (whether participants knew of someone who hadused an epinephrine autoinjector incorrectly) rather than on empir-ical findings. These methods likely resulted in biased comparisons(recall bias) and are also not a valid indication of safety or usability.Fourth, the primary objective of the study was to visually observe“needle injection success” (ie, whether the needle injected or re-tracted by checking for puncture in the paper placed on the orange).However, the authors claim that the NEA needle resides in thepatient for less time than the other 2 products (EpiPen and Twinject)and thus may lessen the potential for injection site reactions (ie,pain, bruising, or bleeding). This statement is indefensible becausethe study did not perform a head-to-head comparison with existingautoinjectors to warrant this claim.
Finally, it is important to iterate that neither of the analyses1,2
evaluated the current EpiPen design (which has a needle protec-tion device that extends and locks into place once the dose isadministered) or addressed the cost of the different devices,particularly for the voice-activated model. We also question theinterpretation of findings because both studies appear to haveconflict of interest: investigator salaries were funded by Intelli-ject in the first study,1 whereas the same funder assisted with thepreparation of the manuscript in the second study.2
On the basis of the possible flaws outlined in these 2 articles,1,2
we believe that further studies with rigorously designed head-to-head comparisons are needed before drawing any conclusions.
SUSAN WASERMAN, MSC, MD, FRCPC*MONIKA KASTNER, PHD†
*Division of Clinical Immunology and AllergyDepartment of MedicineMcMaster UniversityHamilton, Ontario, Canada†Li Ka Shing Knowledge Institute of St. Michael’s HospitalUniversity of TorontoToronto, Ontario, [email protected]
1. Guerlain S, Hugine A, Wang L. A comparison of 4 epinephrine autoinjector deliverysystems: usability and patient preference. Ann Allergy Asthma Immunol. 2010;104:172–177.
2. Guerlain S, Wang L, Hugine A. Intelliject’s novel epinephrine autoinjector: sharpsinjury prevention validation and comparable analysis with EpiPen and Twinject. AnnAllergy Asthma Immunol. 2010;105:480–484.
3. Nielson J. Usability Engineering. New York, NY: Academic Press; 1993.
4. Kushniruk AW, Patel VL. Cognitive and usability engineering methods for theevaluation of clinical information systems. J Biomed Inform. 2004;37:56–78.
VOLUME 107, JULY, 2011
MMEDIATE ALLERGIC REACTIONS TO-LACTAMS: DIAGNOSTIC ACCURACY OF SKINESTS-Lactam antibiotics are the most frequent cause of drug allergic
eactions. During the last few decades, changes in prescribing habitsave caused amoxicillin and amoxicillin-clavulanic to replace ben-ylpenicillin as the most frequently involved agents.1 Skin tests withajor (penicilloyl-polylysine [PPL]) and minor (minor determinantixture [MDM]) penicillin determinants are considered the first
iagnostic procedure in the assessment of immediate allergic reac-ions.2,3 However, in the last few years several authors have de-cribed a decrease in the diagnostic sensitivity of these determi-ants.1 This could be because a significant proportion of patientsroduce specific and selective antibodies against the side chain ofmoxicillin or other �-lactam antibiotics.1 There is some contro-ersy about what determinants should be included in the evaluationf an allergic reaction to �-lactam.3–5
We have evaluated the outcomes of skin tests with different-lactam determinants. In addition, we have assessed whether skin
esting patterns are different in patients with reactions to benzylpen-cillin than in patients with reactions to aminopenicillins.
Between April 1995 and June 2009, we included all patients whoonsulted our Allergy Unit because of a clinical history of anmmediate allergic reaction (anaphylaxis or urticaria) to benzylpen-cillin or aminopenicillins. The study was approved by the ethicsommittee of the hospital, and informed written consent was ob-ained from all patients. To compare the results, the sample wasivided into 2 groups: patients who had had a reaction to benzylpen-cillin (group A) and patients who had had a reaction to aminopeni-illins (group B).
A detailed clinical history was obtained from all the patients. Skinests were performed as previously described,3 with PPL (10-5 M)nd MDM (10-2 M) (Allergopen, Allergopharma, JGKG, Reinbek,ermany, until 2006 and afterward from Diater, Madrid, Spain),enzylpenicillin (10.000 IU), and amoxicillin (20 mg/mL). Initially,kin prick tests were performed. A wheal larger than 3 mm withrythema was considered a positive result. If the skin prick test resultere negative, intradermal tests were performed. A 3-mm change in
he diameter of the initial wheal associated with flare was consideredositive. A positive result to one or more determinants was consid-red diagnostic. When skin test results were negative, a drug prov-cation test with the suspected �-lactam was performed under strictospital surveillance.
Specific IgE to benzylpenicillin and amoxicillin was performedith the CAP-FEIA System (Phadia, Uppsala, Sweden). The posi-
ive cutoff value was 0.35 kUA/L or higher.One thousand thirty-one patients with a suspected immediate
ypersensitivity reaction to BP or aminopenicillins were evaluated.f them, 281 patients (27.2%) had a positive result in the study. Twoundred sixty-four patients (94%) had positive skin test results, and6 patients (5.7%) had a positive challenge test result. Only 1
Disclosures: Dr Moreno has participated in a trial to validate a diagnosticroduct to �-lactam allergy (DAP-REF CEIC:08/731) from Diater Company,lthough the research in this paper is not related in any way to compensationeceived from this company. All other authors do not have any conflict ofnterest.
© 2011 American College of Allergy, Asthma & Immunology.ublished by Elsevier Inc. All rights reserved.
doi:10.1016/j.anai.2011.05.007
89
bod
1
2
3
4
5
6
7
patient’s condition (0.3%) was diagnosed by a positive serum spe-cific IgE result but a negative skin test result.
Skin tests results were positive to penicillin determinants (PPL,MDM, and benzylpenicillin) in 137 patients (48.7%) and to amin-openicillins in 164 cases (58.4%). Among patients with positive skintest results, 83 (33.7%) had positive skin test results exclusively topenicillin determinants, whereas 116 patients (43.9%) had positiveskin test results selectively to aminopenicillins. When analyzing thedifferent determinant involved, amoxicillin was the one that mostfrequently induced a positive skin test result, with an overall per-centage of 58.7% of all positive skin test results, followed by PPL in33.3% of cases and MDM in 28.8%.
When comparing groups A and B, we found that skin test resultswere positive to PPL, MDM, and benzylpenicillin in 90.6% of groupA patients but in only 39% of group B patients (Table 1). On theother hand, skin test results were positive exclusively to amoxicillinin 53.9% of group B patients.
Our results are in agreement with the decrease of the sensitivityof benzylpenicillin determinants observed during the last few de-cades. In a similar population, Blanca et al1,4 found that the percent-age of positive skin test results to PPL and/or MDM decreased from77.7% to 42.1% over the years. This finding could have been due toa change in sensitization patterns secondary to an increase in the useof other �-lactams, mainly aminopenicillins, associated with a con-comitant decrease in the consumption of benzylpenicillin in manycountries.6 According to some publications that recommend per-forming skin tests only with penicillin determinants,7,8 in our series123 patients would have needed a drug provocation test to confirmor rule out �-lactam hypersensitivity.
In conclusion, although a skin test with a penicillin determinant
Table 1. Comparison of Patients With Reactions to Benzylpenicillin (G
Group A (n�53)
PPL/MDMST positive
Other STpositive po
No. (%) of study patients 48 (90.6) 4 (7.5) 1 (1No. (%) men 16 (33.3) 2 (50.0)Age, mean � SD, y 45.00�17.7 46.2�30.5Time elapsed between clinical
reaction and tests, mean� SD, mo
218.2�144.8 105.0�100.6 5
Latency period betweenadministration andsymptoms, mean � SD,min
105.5�266.4 23.7�20.3 Unk
Reaction, No. (%)Urticaria 30 (62.5) 4 (100.0) 1 (1Anaphylaxis 15 (31.2) 0Cutaneous pruritus 3 (6.3) 0
Abbreviations: AM, aminopenicillins; MDM, minor determinant mixturskin tests.
90
ecause of changes in prescribing habits it is necessary to includether �-lactam determinants, mainly aminopenicillins, to correctlyiagnose �-lactam allergy and to avoid ulterior reactions.
ESTHER MORENO, MD, PHD*IGNACIO DÁVILA, MD, PHD*ELENA LAFFOND, MD, PHD*TERESA GRACIA, MD*FRANCISCO MÚÑOZ, MD, PHD*FÉLIX LORENTE, MD, PHD*
*Allergy DepartmentUniversity Hospital of SalamancaSalamanca, [email protected]
. Blanca M, Romano A, Torres MJ, et al. Update on the evaluation of hypersensitivityreactions to betalactams. Allergy. 2009;64:183–193.
. Joint Task Force on Practice Parameters, the American Academy of Allergy, Asthmaand Immunology, the American Academy of Allergy, Asthma and Immunology, andthe Joint Council of Allergy, Asthma and Immunology. Executive summary ofdisease management of drug hypersensitivity: a practice parameter. Ann AllergyAsthma Immunol. 1999;83:665–700.
. Torres MJ, Blanca M, Fernandez J, et al. Diagnosis of immediate allergic reactionsto beta-lactam antibiotics. Allergy. 2003;58:961–972.
. Fox S, Park MA. Penicillin skin testing in the evaluation and management ofpenicillin allergy. Ann Allergy Asthma Immunol. 2011;106:1–7.
. Lin E, Saxon A, Riedl M. Penicillin allergy: value of including amoxicillin as adeterminant in penicillin skin testing. Int Arch Allergy Immunol. 2010;152:313–318.
. Elseviers MM, Ferech M, Vander Stichele RH, Goossens H. Antibiotic use inambulatory care in Europe (ESAC data 1997–2002): trends, regional differences andseasonal fluctuations. Pharmacoepidemiol Drug Saf. 2007;16:115–123.
. Salkind AR, Cuddy PG, Foxworth JW. The rational clinical examination: is thispatient allergic to penicillin? an evidence-based analysis of the likelihood of peni-
A) and Aminopenicillins (Group B)
Group B (n�228)
PPL/MDMST positive
Selective AMST positive
PTpositive
CAPpositive
P value
89 (39) 123 (53.9) 15 (6.6) 1 (0.4) �.00140 (42.1) 65 (49.5) 7 (46.7) NS
38.4�17.7 44.8�17.5 38.0�18.2 NS48.6�74.9 22.4�48.5 33.1�71.9 �.001
105.2�389.3 42.8�70.1 23.9�31.9 NS
59 (66.3) 67 (54.5) 10 (66.7) 1 (100.0)30 (33.7) 56 (45.5) 5 (33.7) .01
0 0
nonsignificant; PT, provocation test; PPL, penicilloyl-polylysine; ST,
continues to be a useful tool in the diagnosis of immediate reactions,cillin allergy. JAMA. 16 2001;285:2498–2505.
8. Greenberger PA. Drug allergy. J Allergy Clin Immunol. 2006;117:S464–S470.
roup
PTsitive
.9)04800
nown
00.0)
e; NS,
ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY
